title: A neuregulin 1 transmembrane domain mutation causes imbalanced glutamatergic and dopaminergic receptor expression in mice.
abstract: The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. In the nucleus accumbens and thalamus Nrg1(+/-) mice exhibited age-dependent alterations in NMDA receptors. Nrg1(+/-) mice showed a statistically significant increase in NMDA receptor levels in the nucleus accumbens of 14-week-old Nrg1(+/-) mice compared to control littermates of the same age (12%, p=0.026), an effect that was not seen in 20-week-old mice. In contrast, NMDA receptor levels in the thalamus, while initially unchanged in 14-week-old mice, were then decreased in the 20-week-old Nrg1(+/-) mice compared to control littermates of the same age (14%, p=0.011). Nrg1(+/-) mutant mice expressed a significant reduction in D2 receptor levels (13-16%) in the striatum compared to controls, independent of age. While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
authors.affiliation: Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, School of Health Sciences, University of Wollongong, NSW 2522, Australia. knewell@uow.edu.au
authors.forename: K A
authors.initials: KA
authors.lastname: Newell
authors.forename: T
authors.initials: T
authors.lastname: Karl
authors.forename: X F
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D009154:Mutation; D020890:Neuregulin-1 / Q000235:genetics* / Q000502:physiology; D017434:Protein Structure, Tertiary; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis; D011954:Receptors, Dopamine / Q000032:analysis*; D011976:Receptors, Muscarinic / Q000032:analysis; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D020890:Neuregulin-1; D043884:Receptor, Cannabinoid, CB1; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate
keywords: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; ANOVA; CB1 receptor; D2 receptor; DISC1; EDTA; EGF; ErbB4; GABA; HEPES; MANOVA; N-methyl-d-aspartate; NMDA; NMDA receptor; Nrg1; Nrg1(+/−); WT; analysis of variance; disrupted in schizophrenia 1; epidermal growth factor; ethylenediamine tetraacetic acid; gamma-aminobutyric acid; heterozygous transmembrane domain neuregulin 1 mutant mouse; mouse; multivariate analysis of variance; neuregulin; neuregulin 1; schizophrenia; v-erb-a erythroblastic leukaemia viral oncogene homologue 4; wild type-like